PROJECT SUMMARY Sensory-guided movements of the arms and hands are essential for many activities of daily living. Pathological processes that impair the cortical circuits mediating these behaviors are a common cause of disability. To better understand and treat these disorders, it will be important to understand the cellular mechanisms in these circuits. Our progress in the previous grant period has helped to elucidate many aspects of the circuit organization of primary motor cortex (M1) neurons in the forelimb area of mouse neocortex. However, a fundamental question remains poorly understood: how are forelimb M1 neurons integrated into functional synaptic circuits with the cells and circuits of primary somatosensory cortex (S1)? This is important to determine, because while the critical importance of somatosensation in controlling movements is well established, the circuits mediating sensorimotor integration in this system are not well characterized. Our working hypothesis is that the forelimb S1?M1 circuit is configured by the cell-type-specific connections of its cortical and thalamic projection neurons to support feedforward somatosensory?motor signaling along complex yet highly specific polysynaptic pathways, leading to excitation of corticospinal neurons. Defining the cellular components of this transcortical loop would be a major step toward elucidating how tactile information is communicated to and integrated by motor cortex neurons to influence cortical output to the spinal cord, in the service of fluid volitional forelimb movements. We propose a research program to test a series of predictions about the cellular organization of the forelimb S1?M1 circuit. The overall aim is to determine the cellular basis for key long-range excitatory circuit connections that mediate communication between forelimb S1 and M1, and between these areas and somatosensory and motor nuclei in the thalamus, particularly the ventral posterior, posterior, and ventrolateral nuclei. To this end, in vivo labeling and ex vivo optogenetic- electrophysiological methods will be used to systematically delineate the cell-type-specific connections mediating thalamus?cortex (Aim 1), cortex?thalamus (Aim 2), and cortex?cortex (Aim 3) communication in this sensorimotor circuit. Overall, the proposed research program is significant and innovative, we believe, because it will generate basic new information about the cellular/synaptic mechanisms underlying the somatosensory?motor transformations at the level of cell-type-specific circuits of the neocortex and thalamus, and thus about the mechanistic basis for sensorimotor functions of the forelimb.